This request for a pilot grant conforms to the priority area of "Animal Models of Aging." The model is a mouse with an inactivating mutation in the colony stimulating factor-1 (CSF-1) gene, resulting in osteopetrosis (op). Within the joint there is also failure of the type A macrophages to develop in the lining layer of the synovial membrane, and absence of osteoclasts and macrophages in the sclerotic subchondral bone beneath the articular cartilage. Injections of the human recombinant CSF-1 protein fail to restore these cellular elements in the joint of the op/op mice. There are two aspects that our studies seek to explore: (1) The possibility that in these op/op mice, dense subchondral bone results in cartilage degeneration - a condition which would provide insight into the pathogenesis of human osteoarthritis where subchondral sclerosis is thought to contribute to cartilage loss. Accordingly, we will compare by Safranin staining the changes in the articular cartilage matrix in young and old op/op mice, a study that takes into account the known influence of aging on the development of human osteoarthritis. (2) The effects in op/op mice of normal, tissue specific expression of transgenes encoding either the CSF-1 proteoglycan form or the membrane-spanning form, whose local actions, in contrast to hormonal effects, may regulate the development of macrophages (F4/80 stain) and osteoclasts (tartrate resistant acid phosphatase stains) within the synovial membrane and subchondral bone, respectively, and also maintain cartilage integrity.